Drug abuse and addiction are significant medical problems in the United States. According to the 2007 National Survey on Drug Use and Health, a reported 19.9 million Americans aged 12 or older were current illicit drug users, meaning that they had used an illicit drug during the month prior to the survey. This estimate represents 0.8 percent of the population aged 12 years old or older. An estimated 3.2 million were classified with dependence on or abuse of both alcohol and illicit drugs, and 3.7 million were dependent on or abused illicit drugs but not alcohol.
Cocaine has one of the highest rates of abuse, and the annual number of new cocaine users continues to steadily increase. In 2007, there were 2.1 million current cocaine users aged 12 or older. Cocaine is a powerfully addictive drug, often leading to severe medical complications including cardiovascular effects, such as disturbances in heart rhythm and heart attacks; respiratory effects such as chest pain and respiratory failure; neurological effects, including strokes, seizures, and headaches; and gastrointestinal complications, such as abdominal pain and nausea. In addition to its direct effects, cocaine abuse has also contributed to the increase of the spread of human immunodeficiency virus (HIV) infection and drug-resistant tuberculosis. As a result, considerable effort has been devoted to the development of a pharmacotherapy to treat patients addicted to cocaine; however, no effective medication is yet available for use in the clinic.
Indirect dopamine agonists have been postulated to be a class of compounds that may show promise for the treatment of cocaine addiction. Studies directed toward the development of indirect dopamine agonists have involved structurally diverse classes of compounds including analogues of 3-phenyltropane, 1,4-dialkylpiperazines, phenylpiperidine, benztropine, methylphenidate, and mazindol.
Bupropion ((±)-2-tert-butylamino-3′-chloropropiophenone, Wellbutrin®) is a well-known antidepressant that has been widely used for the past 30 years. Although the neurochemical mechanisms underlying its action still are not well defined, bupropion is thought to function, at least in part, as an indirect dopamine agonist. It is known to inhibit the reuptake of dopamine (DA) and norepinephrine (NE) but, unlike many other antidepressants, has very little effect on serotonin (5HT) reuptake. Its antidepressant effects have been attributed to its effects on the noradrenergic system, but some reports suggest that bupropion is more potent as a DA reuptake inhibitor than an NE reuptake inhibitor. Microdialysis studies have shown that acute bupropion administration increases extracellular DA. In behavioral pharmacology studies, bupropion has been shown to induce locomotor activity, generalize to cocaine and amphetamine in drug discrimination (DS) studies, produce condition place preference (CPP), and is self-administered in both rats and non-human primates. In addition, bupropion has been reported to increase response on a fixed interval (FI) schedule stimulus-shock termination study in squirrel monkeys. These studies appear to demonstrate bupropion's action as a DA reuptake inhibitor and, thus, indicate that bupropion has the properties of an indirect dopamine agonist.
Bupropion has shown efficacy in addiction. It has been formulated in a sustained release formulation for nicotine addiction and is currently marketed for this purpose as Zyban®. In a clinical trial of bupropion for cocaine abuse, an exploratory analysis suggested that patients with depression may have benefited. Another clinical study has evaluated bupropion-augmented contingency management for cocaine dependence in methadone-maintained patients, finding that the combination of contingency management with bupropion treatment may successfully reduce cocaine use, although there was no evidence for efficacy of bupropion alone. Bupropion has also been studied as a treatment for methamphetamine dependence. In one study, bupropion reduced methamphetamine-induced subjective effects and cue-induced craving. In another study, treatment with bupropion reduced methamphetamine use in relatively light users.
Although bupropion is a successful treatment for both depression and nicotine addiction, relatively few chemical analogues have been prepared and evaluated. Structural analogues of bupropion that function by the same mechanisms of action may be successful in treating depression and nicotine addiction, as well as possibly other related diseases, including addictions of other types and obesity.